Imaging in Rheumatic Immune-related Adverse Events.

Since their introduction, immune checkpoint inhibitors have revolutionized cancer treatment by harnessing the body's own immune system as a defense against tumor growth. The downside of activating the immune system is the development of immune-related adverse events (irAEs), which mimic autoimmune disease of various organ systems. The musculoskeletal system is an uncommon, but substantial one for patients and can lead to long-term pain and disability that affects their quality of life. This review summarizes recent literature on imaging forms utilized for diagnosis and assessing treatment response in rheumatic irAEs.

Cryoablation for the Treatment of Kidney Cancer: Comparison With Other Treatment Modalities and Review of Current Treatment.

With cancer among the leading causes of death worldwide and kidney cancer among the more common cancers in the United States, it has become increasingly important to ensure that first-line treatments remain validated and supported in recent literature. Surgical intervention has long remained the gold standard for intervention but with newer techniques and technology on the horizon, there must be a constant review of other options that may provide improved outcomes and reduction of associated risks. Ablative techniques have gained traction and are becoming a valuable intervention for multiple different types of cancers, kidney cancer included. Cryoablation, a newer ablative technique taking advantage of extreme cold to freeze and destroy abnormal tissue, provides a promising option for treatment. Currently, no review article, to our knowledge, compares all the different treatment options for kidney cancer. Additionally, while some literature has addressed cryoablation in comparison to other methods of management, there has not been an extensive review to combine our current understanding of these comparisons. In this review article, we provide an overview of each of the commonly used treatments for kidney cancer and summarize the current literature regarding the advantages and disadvantages of each intervention. Finally, we seek to compare cryoablation, a newer option for treatment, to each of the approaches with the goal of evaluating the best methods for management and determining cryoablation's role alongside these current interventions.

Stability of Dexmedetomidine in Polyvinyl Chloride Bags Containing 0.9% Sodium Chloride Intended for Subcutaneous Infusions.

Dexmedetomidine is a sedative medication with co-analgesic effects that has been used primarily in critical care and anesthesia as a continuous intravenous infusion. Its utility in the treatment of refractory agitated delirium is being investigated in other settings including palliative care, but continuous intravenous infusions are not always feasible during end-of-life care. Subcutaneous infusions are more commonly used in this setting, but smaller volumes and higher concentrations are typically required. Investigations into stability at these higher concentrations are required to address preparation and administration feasibility issues. The objective of this research was to study the chemical stability of high-concentration dexmedetomidine 20 mcg/mL prepared in polyvinyl chloride bags with 0.9% sodium chloride and storage up to 9 days under refrigeration and room temperature conditions. A total of four solutions of dexmedetomidine 20 mcg/mL in 0.9% sodium chloride were prepared in polyvinyl chloride bags under sterile conditions. Two bags were stored under refrigeration and two bags at room temperature. Duplicate samples were withdrawn from each bag at hours 0, 24, 48, 72, 96, 120, 144, 168, 192, and 216 and frozen at -20°C (total of 4 samples per time point at each storage condition). These samples were thawed and transferred to glass vials prior to their analysis by high-performance liquid chromatography electrospray ionization-tandem mass spectrometry and pH testing. All samples of dexmedetomidine 20 mcg/mL met stability criteria by retaining more than 90% of the initial concentration after 9 days under refrigeration and room temperature. There was no evidence of precipitation or color change during the study period. The pH reduced slightly over time under both refrigerated (5.7 to 4.5) and room temperature conditions (5.7 to 4.6). Dexmedetomidine solutions of 20 mcg/mL intended for subcutaneous use were stable in polyvinyl chloride bags containing 0.9% sodium chloride for 9 days under refrigeration and room temperature.

Improving the clinical relevance of a mouse pregnancy model of antiretroviral toxicity; a pharmacokinetic dosing-optimization study of current HIV antiretroviral regimens.

Animal models can be useful tools for the study of HIV antiretroviral (ARV) safety/toxicity in pregnancy and the mechanisms that underlie ARV-associated adverse events. The utility and translatability of animal model-based ARV safety/toxicity data is improved if ARVs are tested in clinically relevant concentrations. The objective of this work was to improve the clinical relevance of our mouse pregnancy model of ARV toxicity, by determining the doses of currently prescribed ARV regimens that would yield human therapeutic plasma concentrations. Pregnant mice were administered increasing doses of ARV combinations by oral gavage, followed by measurement of drug concentrations in the maternal plasma and amniotic fluid. Concentrations of ten different ARVs in maternal plasma and amniotic fluid samples of pregnant mice are presented, with dosing optimization to yield human pregnancy-relevant plasma drug concentrations. We have proposed optimal dosing for different regimen component drugs to achieve human therapeutic plasma levels, so that a clinically relevant standard dosing is established. A review of related ARV pharmacokinetic studies in (pregnant/non-pregnant) rodents and human pregnancy is also shown. We hope these data will inform and encourage the use of mouse pregnancy models in the study of ARV safety/toxicity.

Poloxamine/fibrin hybrid hydrogels for non-viral gene delivery.

Hydrogels have been widely investigated for localized, sustained gene delivery because of the similarity of their physical properties to native extracellular matrix and their ability to be formed under mild conditions amenable to the incorporation of bioactive molecules. The objective of this study was to develop bioactive hydrogels composed of macromolecules capable of enhancing the efficiency of non-viral vectors. Hybrid hydrogels were prepared by simultaneous enzymatic and Michael-type addition crosslinking of reduced fibrinogen and an acrylated amphiphilic block copolymer, Tetronic T904, in the presence of dithiothreitol (DTT) and thrombin. T904/fibrin hydrogels degraded by surface erosion in the presence of plasmin and provided sustained release of polyplex vectors up to an order of magnitude longer than pure fibrin gel control. In addition, the rate of gel degradation and time-course of polyplex vector release were readily controlled by varying the T904/fibrinogen ratio in the gel composition. When added to transfected neuroblastoma (N2A) cells, both native T904 itself and hydrogel degradation products significantly increased polyplex transfection efficiency with minimal effect on cell viability. To evaluate gel-based transfection, N2A cells encapsulated in small fibrin clusters were covered by or suspended within polyplex-loaded hydrogels. Cells progressively degraded and invaded the hybrid hydrogels, exhibiting increasing gene expression over 2 weeks and then diminishing but persistent gene expression for over 1 month. In conclusion, these results demonstrate that T904/fibrin hybrid hydrogels can be promising tissue engineering scaffolds that provide local, controlled release of non-viral vectors in combination with the generation of bioactive gel degradation products that actively enhance vector efficiency. Copyright © 2014 John Wiley & Sons, Ltd.

Cationic, amphiphilic copolymer micelles as nucleic acid carriers for enhanced transfection in rat spinal cord.

Spinal cord injury commonly leads to permanent motor and sensory deficits due to the limited regenerative capacity of the adult central nervous system (CNS). Nucleic acid-based therapy is a promising strategy to deliver bioactive molecules capable of promoting axonal regeneration. Branched polyethylenimine (bPEI: 25kDa) is one of the most widely studied nonviral vectors, but its clinical application has been limited due to its cytotoxicity and low transfection efficiency in the presence of serum proteins. In this study, we synthesized cationic amphiphilic copolymers, poly (lactide-co-glycolide)-graft-polyethylenimine (PgP), by grafting low molecular weight PLGA (4kDa) to bPEI (25kDa) at approximately a 3:1 ratio as an efficient nonviral vector. We show that PgP micelle is capable of efficiently transfecting plasmid DNA (pDNA) and siRNA in the presence of 10% serum in neuroglioma (C6) cells, neuroblastoma (B35) cells, and primary E8 chick forebrain neurons (CFN) with pDNA transfection efficiencies of 58.8%, 75.1%, and 8.1%, respectively. We also show that PgP provides high-level transgene expression in the rat spinal cord in vivo that is substantially greater than that attained with bPEI. The combination of improved transfection and reduced cytotoxicity in vitro in the presence of serum and in vivo transfection of neural cells relative to conventional bPEI suggests that PgP may be a promising nonviral vector for therapeutic nucleic acid delivery for neural regeneration. STATEMENT OF SIGNIFICANCE: Gene therapy is a promising strategy to overcome barriers to axonal regeneration in the injured central nervous system. Branched polyethylenimine (bPEI: 25kDa) is one of the most widely studied nonviral vectors, but its clinical application has been limited due to cytotoxicity and low transfection efficiency in the presence of serum proteins. Here, we report cationic amphiphilic copolymers, poly (lactide-co-glycolide)-graft-polyethylenimine (PgP) that are capable of efficiently transfecting reporter genes and siRNA both in the presence of 10% serum in vitro and in the rat spinal cord in vivo. The combination of improved transfection and reduced cytotoxicity in the presence of serum as well as transfection of neural cells in vivo suggests PgP may be a promising nucleic acid carrier for CNS gene delivery.

Efficacy and mechanism of poloxamine-assisted polyplex transfection.

BACKGROUND: Amphiphilic block copolymers acting as biological response modifiers provide an attractive approach for improving the transfection efficiency of polycationic polymer/DNA complexes (polyplexes) by altering cellular processes crucial for efficient transgene expression. METHODS: The present study aimed to investigate the effect of the poloxamine Tetronic T904, a four-arm polyethylene oxide/polypropylene oxide block copolymer, on polyplex transfection and to determine its mechanism of action by analyzing the cellular uptake of polyplex, the nuclear localization of plasmid and RNA transcript production. RESULTS: T904 significantly increased the transfection efficiency of polyplexes based on 25-kDa branched polyethylenimine in a dose-dependent manner in the presence of serum in C6 glioma cells, as well as human fibroblasts and mesenchymal stem cells. The activity of T904 was not promoter-dependent, increasing the expression of reporter genes under both cytomegalovirus and SV40 promoters. Although T904 did not affect the internalization or nuclear uptake of plasmid, mRNA expression levels from both promoters showed dose-dependent increases that closely paralleled increases in gene expression. CONCLUSIONS: The present study demonstrates that T904 significantly increases polyplex transfection efficiency and suggests a mechanism of increased transcriptional activity. As a four-arm, hydroxyl-terminated polymer, T904 is amenable to a variety of end group functionalization and covalent cross-linking strategies that have been developed for preparing hydrogels from multi-arm polyethylene glycol, making it particularly attractive for scaffold-mediated gene delivery.